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Liver Microvascular Injury and Thrombocytopenia of Antibody–Calicheamicin Conjugates—Mechanism

From:DAC Biotech  Time:2017-07-12 09:19:44

Purpose: Adverse reactions reported in patients treated with antibody–calicheamicin conjugates such as gemtuzumab ozogamicin (Mylotarg) and inotuzumabozogamicin include thrombocytopenia and sinusoidal obstruction syndrome (SOS). The objective of this experimental work was to investigate the mechanism forthrombocytopenia, characterize the liver injury, and identify potential safety biomarkers. Experimental Design: Cynomolgus monkeys were dosed intravenously at6 mg/m2/dose once every 3 weeks with a nonbinding antibody–calicheamicin conjugate (PF-0259) containing the same linker-payload as gemtuzumabozogamicin and inotuzumab ozogamicin. Monkeys were necropsied 48 hours after the first administration (day 3) or 3 weeks after the third administration (day63). Results: PF-0259 induced acute thrombocytopenia (up to 86% platelet reduction) with nadirs on days 3 to 4. There was no indication of effects on megakaryocytes in bone marrow or activation of platelets in peripheral blood. Microscopic evaluation of liver from animals necropsied on day 3 demonstratedmidzonal degeneration and loss of sinusoidal endothelial cells (SECs) associated with marked platelet accumulation in sinusoids. Liver histopathology on day 63 showed variable endothelial recovery and progression to a combination of sinusoidal capillarization and sinusoidal dilation/hepatocellular atrophy, consistent with early SOS. Among biomarkers evaluated, there were early and sustained increases in serum hyaluronic acid (HA) that correlated well with serum aspartate aminotransferase and liver microscopic changes, suggesting that HA may be a sensitive diagnostic marker of the liver microvascular injury.

Conclusion: These data support the conclusion that target independent damage to liver SEC(窦状内皮细胞may be responsible for acute thrombocytopenia (through platelet sequestration in liver sinusoids) and development of SOS (肝窦阻塞综合征).

Magali Guffroy, etc


Clin Cancer Res; doi: 10.1158/1078-0432.CCR-16-0939